Fig. 1.

Biogenesis of lamin A from prelamin A. Prelamin A undergoes four posttranslational processing steps (13). First, the cysteine of the C-terminal CaaX motif is farnesylated by protein FTase. Second, the last three amino acids (-aaX) are clipped off (cleavage P1), a redundant activity of RCE1 and ZMPSTE24 (13). Third, the farnesylcysteine is carboxyl-methylated by ICMT. Fourth, the last 15 amino acids of prelamin A (including the farnesylcysteine methyl ester) are clipped off by ZMPSTE24 (cleavage P2), releasing mature lamin A. Lonafarnib, an FTI, blocks all of the processing steps and leads to the accumulation of nonfarnesylated prelamin A. In this study, we tested the hypothesis that HIV-PIs inhibit ZMPSTE24, causing an accumulation of farnesyl-prelamin A in cells.